The dosing of drugs is carried out in a number of different ways in the medical service today. Within health-care, there is a rapidly growing interest in administering locally or systemically acting medication in prescribed doses of powder directly to the airways and lungs of a patient by means of an inhaler in order to obtain an effective, quick and user-friendly administration of such drugs.
A dry powder inhaler, DPI, represents a device intended for administration of doses of powder into the deep and/or upper lung airways by oral inhalation. However, deep lung deposition of medicament is a more difficult proposition and has only recently come into focus. Most inhalers on the market today are designed for treatment of ailments in the airways or local lung, like asthma, where the objective often is local, not deep lung, deposition. When the objective is a systemic delivery of the medication, then a deep lung deposition of the powder is preferred and usually necessary for maximum efficiency. The deep lung is defined as the peripheral lung and alveoli, where direct transport of a substance to the blood can take place. If a particle is to reach into the deep lung the aerodynamic particle size should typically be less than 3 μm, and for a local lung deposition, typically about 5 μm. Larger particle sizes will easily stick in the mouth and throat. Thus, regardless of whether the objective is a local or systemic delivery of a drug, it is important to keep the particle size distribution of the dose within tight limits to ensure that a high percentage of the dose is actually deposited where it will be most effective.
Particle size is especially important for a successful delivery to the deep lung upon inhalation. Furthermore, for optimal results, the inspiration must take place in a calm manner to decrease air speed and thereby reduce deposition by impaction in the upper respiratory tracts. The advantages of using the inhalation power of the user to full potential in a prolonged, continuous dose delivery interval within the inhalation cycle is disclosed in our Swedish Patent no. SE 9904081-8 (WO 01/34233 A1), which is hereby incorporated herein by reference. The patent presents several devices for efficient distribution of pharmaceutical compositions in fine powder form in the inspiration air, without using other sources of energy than the power of the air in the user's inhalation.
Powders for inhalation have a tendency of aggregating, in other words to clod or to form smaller or larger lumps of particles, which then have to be de-aggregated before the particles enter into the mouth of the user. De-aggregating is defined as breaking up aggregated powder by introducing energy; e.g. electrical, mechanical, pneumatic or aerodynamic energy. To succeed with systemic delivery of medication powders by inhalation to the deep lung, it is important to achieve a high degree of de-aggregation of the medication powder in the inhaled air. In most cases, treatment of a patient is not a single occurrence, but has to be repeated and in some chronic cases, treatment has to be on a continuous basis. In all cases, de-aggregation must be very repeatable and dosing must be kept within tight tolerances from one administration to the next.
A majority of dry powder inhalers of today presents rather moderate deaggregation capacity. Current inhalation devices intended for asthma and other lung diseases normally deliver the dispensed drug particles in a larger size range than optimal for deep lung deposition. This is often caused by inadequate de-aggregation of powder particle aggregates with a primary particle size in the range 2-3 μm. Thus, the inhaled dose consists of aggregates of smaller particles. This entails several disadvantages:                The uniformity of aerodynamic particle size distribution between different doses may vary considerably, because the de-aggregation is sensitive to slight difference in inspiration conditions from one inhalation to the next.        Particle size distribution of the delivered dose may have a tail of big aggregates, which will deposit in the mouth and upper airways.        Retention of the substance in the inhaler may vary with the aerodynamic particle size distribution and may hence be difficult to predict.        
Thus, for a consistent, predictable and repeatable delivery of medicaments to the lungs there is a need of a de-aggregating method capable of producing reproducibly a very high degree of de-aggregation of the dry powder medicament. This is especially true for systemically acting drugs, where a deep lung deposition is normally required. In addition, for locally acting medicaments, where usually a local lung deposition is preferred, a high degree of de-aggregation of the medication powder is an advantage. Preferably, the de-aggregating method ought to be insensitive as far as possible to the inhalation effort produced by the user, such that the delivered aerodynamic particle size distribution in the inhaled air is independent of the inhalation effort. The average aerodynamic particle size, which influences the deposition pattern in the lungs, can be controlled by controlling the primary particle size distribution of the particles constituting the powder.
Introducing special devices as for example spacers and/or external sources of energy to amplify the inhalation energy provided by the user during the act of inhalation are common methods in prior art inhalers for improving the performance in terms of de-aggregation and dosing predictability and repeatability. The addition of external sources of energy leads to more complex and expensive inhalers than necessary, besides increasing the demands put on the user in maintaining the inhaler.
Over the years, many methods and devices have been tried in order to improve the performance of drug delivery systems based on inhalation. For instance, U.S. Pat. No. 480,505, dated as early as Aug. 9, 1892, describes a nasal respirator device, including reticulated material and adapted to receiving a porous medium impregnated with medicine. Nets, screens or membranes with interstices are well known to a person skilled in the art, as components in many inhaler designs, either as carriers of drugs or elements to facilitate the release of the dose to a user. An example of a prior art inhaler device using a perforated membrane as a dispensing element for an active compound of medicament is disclosed in a European patent EP 0 069 715 B1 with priority date Aug. 7, 1981. The patent teaches an inhaler comprising a nozzle, an air conduit and a displaceable dispensing element in the form of a perforated membrane, for dispensing the medicament from a storage chamber into the air conduit. Dry powder inhaler medicament carriers with interstices for enhancement of de-aggregation of a powder dose are dealt with in several later documents e.g. U.S. Pat. Nos. 5,388,572; 5,388,573; 5,460,173; 5,647,347; 5,823,182; 6,245,339 B1 and WIPO publication Nos. WO94/20164; WO98/04308. The carriers and methods, taught in the referred documents, are characterized in that the powdered medicament is impregnated or embedded in and across interstices at spaced locations in the carrier, thus forming one or more doses of medicament. A dose is then put in a flow channel connected to a mouthpiece. As the user inhales through the mouthpiece the created air stream forces the aggregated dry powder particles of the dose loaded onto or into the carrier to be released into air and de-aggregated by the shearing force of the air as it passes through the interstices and past the aggregated powder particles. Thus, a main purpose of the net or screen type of carrier presented in the referred documents is to facilitate de-aggregation of the dose. However, examples in some of the documents show pressure chambers or similar means for creating a high-pressure air pulse, 70 psig (=490 kPa) in one case, necessary to blow the dose off the carrier. A pressure of 70 psig is about 100 times higher than the pressure drop produced by the inhalation of a user. A normal inspiration by an adult produces about 5 kPa and an external energy source is therefore necessary in order to produce the air pulse. The suggested methods seem to be limited in terms of dose mass, only being suitable for rather small doses. The teachings also suggest using ordered mixtures of active substance and some excipient, to further improve de-aggregation, which further limits the active medicament mass in the dose.
Another example of an inhalation device addressing the problem of de-aggregation is disclosed in U.S. Pat. No. 5,694,920 and further improvements of the inhaler are disclosed in U.S. Pat. Nos. 6,026,809 and 6,142,146. The inventions teach that de-aggregation of a medication powder may be provided by a vibrator, which directly or indirectly imparts mechanical energy of suitable frequency and power to the powder. The powder is thus fluidized and de-aggregated. Particles of a size suitable for inhalation are then lifted out from the fluidized powder and introduced in an air stream by an electric field of suitable strength established across the air stream. The particles are then delivered to a user by the air stream. Clearly, it is necessary to provide external power in electro-mechanical form to achieve de-aggregation, which still seems to be only partially successful.
Prior art methods and devices leave much to be desired when it comes to dose conformity, particle de-aggregation and efficient administration of the medication substance. Furthermore, prior art methods of de-aggregating and dispersing into air a dose seem to require high levels of de-aggregating energy, which lead to more or less complicated inhaler designs. Furthermore, achieving an objective of efficient de-aggregation in terms of percentage mass of particles less than 5 μm dispersed into air relative to available powder mass seems to be a far way off. Till the present day too little has been done to develop user friendly, highly efficient methods and devices for de-aggregating and dispersing into air a quantity of medication powder, especially when using the effort of the user's inhalation as the single source of energy.